CN111920796A - 化合物在制备治疗癫痫药物中的应用 - Google Patents
化合物在制备治疗癫痫药物中的应用 Download PDFInfo
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Abstract
本发明公开了化合物在制备治疗癫痫药物中的应用，具体的，式(I)所示的化合物、其药学上可接受的盐或其前药在制备预防和/或治疗癫痫和/或癫痫并发症药物中的应用，经实验证明：本发明的化合物有效减少癫痫小鼠模型自发性异常放电的频率。本发明的抗癫痫的化合物在预防和/或治疗癫痫和/或癫痫并发症方面，具有很好的疗效。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种化合物在制备治疗癫痫药物中的应用。
背景技术
癫痫(Epilepsy)是一种由于大脑神经元突发性异常放电，导致短暂的大脑功能障碍的慢性脑部疾病，会突然间毫无征兆地发作，且在任何年龄段的人群均可发病，是最常见的神经系统疾病之一。癫痫发作导致了脑内神经环路和活动的异常，使患者遭受认知、情绪和精神紊乱，不仅严重影响患者的正常工作和生活，也缩短了患者的平均寿命。因此，癫痫一直是一个重要社会问题和全球经济负担，癫痫的发病机制及治疗策略也是研究者的重点关注对象。
癫痫发作的临床表征主要为中枢神经系统局部或整个脑区神经元的异常同步化放电。神经元间的电活动平衡主要由兴奋性和抑制性神经元的活动彼此相互牵制形成，脑内兴奋性活动的增强或抑制性活动的减弱均会影响神经网络环路的电平衡。离子通道是担负中枢神经系统兴奋性活动(即神经元动作电位的传导)以及形成神经环路(即神经元间突触信号的传递)的核心构件，任何离子通道的基因突变都有可能异化通道蛋白的正常功能，造成中枢神经系统电活动的失衡，最终诱发异常同步化放电。
电压门控钠通道在神经元中产生动作电位，其功能失调可引起遗传性癫痫、慢性疼痛等过度兴奋性疾病。因而，目前常用于临床的一大类抗癫痫药物，其机制即是选择性作用于钠通道，阻断钠离子依赖性动作电位的快速发放，调节电压依赖性钠离子通道。此外，这些药物还可以阻断钙离子通道，调节Na+-K+-ATP转化酶活性，从而达到抗惊厥作用。
发明内容
为此，本发明提供化合物在制备治疗癫痫药物中的应用。
为了实现上述目的，本发明提供如下技术方案：
本发明提供的式(I)所示的化合物、其药学上可接受的盐或其前药在制备预防和/或治疗癫痫和/或癫痫并发症药物中的应用，
本发明的一个实施例中，所述化合物、其药学上可接受的盐或其前药在制备预防和/或治疗癫痫的产品；
抑制电压门控钠离子通道NaV1.8的产品；以及
调节电压门控钠离子通道NaV1.8的产品。
本发明的一个实施例中，所述癫痫并发症包括生殖功能低下、神经内分泌功能紊乱和神经精神障碍。
上述所述的化合物、其药学上可接受的盐或其前药有效剂量组成的药物组合物，其中含有一个或多个药学上可接受的药物载体。也属于本发明保护的范围
本发明的一个实施例中，其中，所述药物载体包括：稀释剂、赋形剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、润滑剂。
本发明的一个实施例中，其中，所述药物组合物的剂型为片剂、胶囊、口服液、注射剂、粉剂、膏剂或外用药液。
本发明中，术语“前药”是指一种作为药物前体的化合物，该化合物在被服用后，在体内通过代谢或化学过程(例如，被置于生理pH条件下或通过酶的活性)发生化学转化，释放活性药物。。本发明的“前药”也可包括本发明化合物的代谢前体，该类前药在对主体给药时可能不具有活性，但可在体内转化为本发明的式(I)化合物或其盐和/或溶剂化物。前药也可以是天然存在或者化学合成的化合物。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指式(I)所示的化合物或其立体异构体，或其前药与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将式(I)所示化合物，或其立体异构体，或其前药，与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。
本发明的化合物所述治疗的肿瘤不是所有肿瘤，而是特定的肿瘤，如通过特定机制而能够凋亡的肿瘤。根据试验结果，式(I)化合物的体外抗肿瘤细胞增殖作用是通过抑制IKKβ所导致的。式(I)化合物(D6)可以直接结合于IKKβ，并抑制其磷酸化下游底物，继而减少所调控基因(Bcl-2)的表达，并激活Caspase家族特异性切割底物PARP，从而显著诱导肿瘤细胞凋亡。在细胞实验中，式(I)化合物对多种特定肿瘤细胞的增殖抑制活性皆能达到单微摩尔级别。
本发明中，所述药学上可接受的载体是指药学领域常规的药物载体，例如：稀释剂、赋形剂如水等，填充剂如淀粉、蔗糖等；粘合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮；湿润剂如甘油；崩解剂如琼脂、碳酸钙和碳酸氢钠；吸收促进剂如季铵化合物；表面活性剂如十六烷醇；吸附载体如高岭土和皂粘土；润滑剂如滑石粉、硬脂酸钙/镁、聚乙二醇等。另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
本发明药物组合物的形式通过口服，鼻吸入、直肠或者肠胃外给药的方式施用于需要这种治疗的患者。用于口服时，可将其制成常规的固体制剂如片剂、粉剂、粒剂、胶囊等，制成液体制剂如水或油悬浮剂或其它液体制剂如糖浆、酏剂等；用于肠胃外给药时，可将其制成注射用的溶液、水或油性悬浮剂等。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种载体混合，然后将其制成所需的剂型。
本发明具有如下优点：
经实验证明：本发明的化合物有效减少癫痫小鼠模型自发性异常放电的频率。本发明的抗癫痫的化合物在预防和/或治疗癫痫和/或癫痫并发症方面，具有很好的疗效。
附图说明
为了更清楚地说明本发明的实施方式或现有技术中的技术方案，下面将对实施方式或现有技术描述中所需要使用的附图作简单地介绍。显而易见地，下面描述中的附图仅仅是示例性的，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据提供的附图引伸获得其它的实施附图。
图1为本发明实施例首次急性腹腔注射10mg/kg体重的本发明的抗癫痫的化合物A-803467脑电波效果图；
图2为本发明实施例的停止给药前及停止给药三天后模型小鼠的脑电波效果图；
图3为本发明实施例的给药前后模型小鼠的脑电图中平均每小时的Spikes数目、平均每天的SRS数目统计柱状图。
具体实施方式
以下由特定的具体实施例说明本发明的实施方式，熟悉此技术的人士可由本说明书所揭露的内容轻易地了解本发明的其他优点及功效，显然，所描述的实施例是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
本发明实施例提供一种具有优异抗癫痫效果的小分子化合物：A-803467，编号T2024，别名：A803467、A 803467，CAS 944261-79-4，分子式C19H16ClNO4，分子量357.79，靶点：电压门控钠离子通道NaV1.8。
本发明的化合物的化学式如式(I)所示，A-803467是电压门控钠离子通道NaV1.8的选择性抑制剂。
本发明实施例的化学式如式(I)所示的化合物，作为注射剂使用，其注射剂量是10mg/kg体重。
实施例2、化合物有效减少癫痫小鼠模型自发性异常放电的频率
本实施例实验的具体步骤为：
一、实验过程
实验动物：C57BL/6J小鼠(8-10周)购自上海斯莱克实验动物有限责任公司，所有小鼠的饲养根据标准规章制度进行，所有针对动物的实验程序按照南京医科大学实验动物福利伦理委员会的指导原则执行。
试剂与耗材：实验中用到的试剂A-803467购自上海陶术生物科技有限公司，货号T2024；毛果芸香碱盐酸盐(Pilocarpine hydrochloride,Pilocarpine)购自Sigma，货号P6503；东良宕碱甲基硝酸(Scopolamine methyl nitrate,Scopolarmine)购自Tcichemicals，货号S0230；阿托品甲基硝酸酯(Atropine methyl nitrate,Atropine)购自Sigma，货号SML0732；特布他林半硫酸盐(Terbutaline hemisulfate salt,Terbutulin)购自Sigma，货号T2528；地西泮购自医院。
本实施例中，用到的设备EEG脑电波检测仪购自Nihon Kohden，型号EEG1200C；螺钉电极购自PlasticOne，货号E363-96-2.4-SPC，长度6.5mm；直电极购自PlasticOne，货号E363T-2-SPC，长度7.5mm；电极底座购自PlasticOne，货号MS363；电极转换器购自PlasticOne，货号SL6C；电极连接器电缆购自PlasticOne，货号363-441/6，长度3m。
步骤一、毛果芸香碱(Pilocarpine)皮下注射构建小鼠自发性癫痫模型
Pilocarpine为胆碱能肌肉激动剂，全身给药可引起癫痫发作，Pilocarpine模型是目前应用最多的癫痫持续状态模型及自发发作模型。它发生发展过程与人类颞叶癫痫高度相似，具有相同的病理学基础，对大部分抗癫痫药物耐药，是研究颞叶癫痫的理想工具。
癫痫模型发作等级评判小鼠癫痫发作等级评分采用Racine等级评判标准：0级：奔跑正常，无任何其他非应激性反应；一级：面部肌肉阵挛、颤动，如眨眼、胡须跳动、节律性咀嚼等；二级：一级发作加呈节律性点头、前肢阵挛；三级：二级发作加前肢肌阵挛但没有后肢直立动作；四级：三级加后肢直立动作，伴有斜行双侧、摔倒；五级：全身强直，摔倒，失平衡，翻滚并失去体位，四肢抽搐。三级及以上判定为重度发作，为成功的癫痫模型，用于后续实验。
称量小鼠体重，小鼠的体重很关键，22-28g小鼠最合适，全部使用雄性小鼠。腹腔注射Scopolarmine、Atropine、Terbutulin，剂量是2mk/kg体重，需要记录注射时间，30分钟后注射pilocarpine。皮下注射Pilocarpine，剂量是280mg/kg体重，然后密切观察2-3小时期间小鼠抖动情况，评判癫痫发作等级。
3h后，给予小鼠腹腔注射地西泮终止痫性发作，剂量是0.01mg/只，选取三级及以上的小鼠继续饲养并用于EEG电极植入和检测。
步骤二、癫痫模型小鼠头部植入EEG电极
EEG(Electroencephalogram)，脑电波监测是研究癫痫小鼠脑部电活动的有效方式之一，Pilocarpine造模后75天左右开始EEG记录与分析。
在脑电记录前一周，在小鼠麻醉状态下，用脑立体定位仪定向将五个记录电极：左右皮层各1个，前额皮层1个，左右海马各1个，植入小鼠颅内。然后，将电极连接到连接器底座，该底座用牙科水泥固定在颅骨上。在进一步的操作和长时间的脑电图监测开始之前，让小鼠在24-72小时内不受限制，以便从手术中恢复。
将小鼠头顶连接器底座通过转换器、连接器电缆连接到EEG脑电波检测仪，使用EEG2100软件进行数字脑电图记录与分析。首先记录给药前(pre-drug)持续3天内每只模型小鼠的脑电图，全身自发性癫痫发作定义为持续在所有电极上超过3秒的重复性癫痫样发作活动(>3Hz)，选取出现自发性癫痫发作脑电波的小鼠作为成功的癫痫模型。然后，每天一次、连续3天腹腔注射本发明的抗癫痫效果的小分子化合物A-803467，剂量是10mg/kg体重，并持续记录小鼠的连续脑电图。最后，记录给药后(Post-drug)连续3天的小鼠脑电图。在记录过程中，小鼠自由活动，可以随意获取食物和水。
二、实验结果
1、如图1所示，首次急性腹腔注射10mg/kg体重的本发明的抗癫痫效果的小分子化合物A-803467脑电波效果图，Pilocarpine造模后2.5个月，癫痫模型小鼠发展出稳定的癫痫脑电波(spikes，即在所有电极上出现单个高波幅、尖锐的棘状波，后跟一个慢波)和自发性癫痫发作脑电波，即spontaneous recurrent spikes，SRS，即一群持续在所有电极上超过3秒的重复性癫痫脑电波。
给予癫痫模型小鼠首次急性腹腔注射10mg/kg体重的A-803467，20分钟后，Spikes开始波幅下降，数量减少，30分钟后Spikes显著波幅下降，数量减少，40分钟后脑电波短暂趋于正常。
如图2所示，停药三天后模型小鼠的脑电波效果图，给予癫痫模型小鼠每天一次、连续3天腹腔注射10mg/kg体重的本发明的抗癫痫效果的小分子化合物A-803467，在停药三天后Spikes和SRS与给药前(Pre-drug)相比，均数量显著降低，即模型小鼠的癫痫发作被显著抑制。
如图3所示，给药前后模型小鼠的脑电图中平均每小时的Spikes数目，平均每天的SRS数目统计图，记录给药前持续3天内每只模型小鼠(N＝5)的脑电图，并统计平均每小时的Spikes数目，平均每天的SRS数目。给予癫痫模型小鼠每天一次，连续3天腹腔注射10mg/kg体重的本发明的抗癫痫效果的小分子化合物A-803467，然后，记录停药后持续3天内每只小鼠的脑电图，并统计平均每小时的Spikes数目、平均每天的SRS数目。结果显示Spikes和SRS在给药后(Post-drug)均数量显著降低，即给药后模型小鼠的癫痫发作被显著抑制。
实验证明，本发明的抗癫痫效果的小分子化合物A-803467可以有效减少癫痫小鼠模型自发性异常放电的频率，能够有效抑制模型小鼠的癫痫发作。
虽然，上文中已经用一般性说明及具体实施例对本发明作了详尽的描述，但在本发明基础上，可以对之作一些修改或改进，这对本领域技术人员而言是显而易见的。因此，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明要求保护的范围。
Claims (6)
1.式(I)所示的化合物、其药学上可接受的盐或其前药在制备预防和/或治疗癫痫和/或癫痫并发症药物中的应用，
式(I)。
2.如权利要求1所述的应用，其特征在于，
所述化合物、其药学上可接受的盐或其前药在制备预防和/或治疗癫痫的产品；
制备抑制电压门控钠离子通道NaV1.8的产品；以及
制备调节电压门控钠离子通道NaV1.8的产品。
3.如权利要求1所述的应用，其特征在于，
所述癫痫并发症包括生殖功能低下、神经内分泌功能紊乱和神经精神障碍。
4.权利要求1或2所述的化合物、其药学上可接受的盐或其前药有效剂量组成的药物组合物，其中含有一个或多个药学上可接受的药物载体。
5.如权利要求3所述的药物组合物，其中，所述药物载体包括：稀释剂、赋形剂、粘合剂、湿润剂、吸收促进剂、表面活性剂、润滑剂。
6.如权利要求4所述的药物组合物，其中，所述药物组合物的剂型为片剂、胶囊、口服液、注射剂、粉剂、膏剂或外用药液。
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